A Phase Ib/IIa Study of Rucaparib (PARP Inhibitor) Combined With Nivolumab in Metastatic Castrate - Resistant Prostate Cancer and Advanced/Recurrent Endometrial Cancer
Overview
- Phase
- Phase 1
- Intervention
- Rucaparib
- Conditions
- Prostate Cancer
- Sponsor
- University of Chicago
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Percentage of Participants With Dose Limiting Toxicities (DLT) (Phase 1)
- Status
- Terminated
- Last Updated
- 5 years ago
Overview
Brief Summary
This is a phase 1/phase 2a study of the combination of immune checkpoint inhibitor (nivolumab) in combination with the PARP inhibitor (rucaparib) for patients with metastatic castration resistant prostate cancer (mCRPC) and metastatic/recurrent endometrial cancer.
In the phase 1 portion, the safety of the combination dosing will be determined. If the combination dosing is determined to be safe and feasible, the study will move onto phase 2a.
In the phase 2a portion, participants will be randomized to receive either: rucaparib alone, nivolumab alone, or combination therapy (rucaparib and nivolumab).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have the ability to understand and the willingness to signed a written informed consent document.
- •Patients must have histologically or cytologically confirmed CRPC or endometrial cancer that is metastatic. Evidence of disease progression on a prior therapy is not required.
- •Patients must have at least one lesion that is amenable to biopsy and the treating physician must deem this safe.
- •Patient must be willing to undergo two mandatory research-only biopsies.
- •Prostate cancer patients:
- •Patients must be surgically or medically castrated, with serum testosterone levels ≤ 50 ng/mL Patients being treated with Gonadotropin-releasing hormone (GnRH) agonists must have such therapy continued throughout the study.
- •Patients should have received at least one androgen receptor (AR)-targeted therapy with abiraterone acetate or enzalutamide. Multiple lines of prior AR-targeted therapy and chemotherapy are permitted. A washout of two weeks from prior endocrine therapy (other than GnRH agonist); four weeks washout period from prior cytotoxic chemotherapy or other anticancer agents is required (prior to day 1 of study therapy); six weeks washout period to allow for anti-androgen withdrawal for patients managed with antiandrogen therapy such as bicalutamide.
- •Endometrial cancer patients:
- •An unlimited number of prior hormonal and/or chemotherapy regimens are permitted. A washout of two weeks from prior endocrine therapy (other than GnRH agonist) and four weeks from prior cytotoxic chemotherapy or other anticancer agents is required (prior to day 1 of study therapy).
- •At least 5 days should have elapsed since any non-study related minor surgical procedure and at least 21 days since any major surgical procedure prior to the first dose of rucaparib and the first dose of nivolumab.
Exclusion Criteria
- •Patients with active, known, or suspected autoimmune disease. Subjects with vitiligo, type I diabetes, mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, childhood asthma that is not currently active, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
- •Patients with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration except for adrenal replacement steroid doses \> 10 mg daily prednisone equivalent in the absence of active autoimmune disease. Note: Treatment with a short course of steroids (\< 5 days) up to 7 days prior to initiating study drug is permitted.
- •Patients who are receiving any other investigational agents.
- •Prior exposure to PD-1 or PD-L1 inhibitors, other immune checkpoint inhibitors (e.g. anti-LAG-3, and anti-CTLA-4 antibodies), or PARP inhibitors.
- •Patients with a "currently active" second invasive malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy if they have completed therapy and have been free of disease for ≥ 1 years.
- •Patients with known and untreated or progressing brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients whose brain metastases have been treated with surgery and/or radiotherapy and are without evidence of progression on scan for at least 4 weeks, and are off steroids or antiseizure medications, will be eligible .
- •Patients with symptomatic or impending spinal cord compression are not eligible unless appropriately treated.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab or rucaparib.
- •Based on in vitro CYP interaction studies, caution should be used for concomitant medications with a narrow therapeutic window that are substrates of CYP2C19, CYP2C9, and/or CYP3A. Selection of an alternate concomitant medication is recommended. Caution should also be exercised for concomitant use of certain statin drugs (e.g. rosuvastatin and fluvastatin) due to potential increase in exposure from inhibition of BCRP and CYP2C
- •An updated list of clinically relevant P450 drug interactions (e.g: Flockhart Table http://medicine.iupui.edu/clinpharm/ddis/main-table/) should be reviewed while screening patients for study.
Arms & Interventions
Combination Therapy (Phase 1b Cohort)
Participants will receive rucaparib plus nivolumab in 4 week cycles.
Intervention: Rucaparib
Combination Therapy (Phase 1b Cohort)
Participants will receive rucaparib plus nivolumab in 4 week cycles.
Intervention: Nivolumab
Rucaparib (Phase 2b Randomized Cohort)
Participants randomized to receive rucaparib alone in 4 week cycles.
Intervention: Rucaparib
Nivolumab (Phase 2b Randomized Cohort)
Participants randomized to receive nivolumab alone in 4 week cycles.
Intervention: Nivolumab
Combination Therapy (Phase 2b Randomized Cohort)
Participants randomized to receive rucaparib plus nivolumab in 4 week cycles. Participants will receive rucaparib alone in cycle 1 and begin nivolumab on day 1 of Cycle 2.
Intervention: Rucaparib
Combination Therapy (Phase 2b Randomized Cohort)
Participants randomized to receive rucaparib plus nivolumab in 4 week cycles. Participants will receive rucaparib alone in cycle 1 and begin nivolumab on day 1 of Cycle 2.
Intervention: Nivolumab
Outcomes
Primary Outcomes
Percentage of Participants With Dose Limiting Toxicities (DLT) (Phase 1)
Time Frame: 8 weeks
Dose limiting toxicities (DLT) is measured by patients with grade 3 or 4 toxicity within 4 weeks of starting leading to discontinuation of rucaparib for at least 1 week
Frequency of Patients With T Cell Inflammation in the Tumor Compared Between Treatment Arms (Phase 2)
Time Frame: 4 weeks
Secondary Outcomes
- Time to Disease Progression in Prostate Cancer Patients (Phase 2)(24 months)
- Time to Disease Progression in Endometrial Cancer Patients (Phase 2)(24 months)
- Response Rate in Prostate Cancer Patients (Phase 2)(24 months)
- Response Rate in Endometrial Cancer Patients (Phase 2)(24 months)
- Changes in Number of T Cells in Tumor Samples Compared Between Treatment Arms (Phase 2)(4 weeks)
- Correlation of Change in T Cells in Tumor Samples and PTEN Mutation Status (Phase 2)(4 weeks)